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JoAnn Sekiguchi

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Primary Appointment: Int Med-Molecular Med&Genetics
Primary PIBS Dept.: Human Genetics
Other PIBS Depts.: Cancer Biology
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  Our lab studies mechanisms of DNA repair and how aberrant repair processes affect genomic stability, predisposition to cancer and immune system development. The projects in the lab are focused on characterizing the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair, one of the two major pathways of double strand break repair in mammalian cells. The NHEJ factors are not only required for general DNA repair, but also play critical roles during early B and T lymphocyte development and in maintaining genomic stability. Thus, mutations in the NHEJ genes are known to cause human immunodeficiency disorders and are also associated with predisposition to cancer in human patients. We use the mouse as a model system to study the biological consequences of specific targeted mutations in the NHEJ genes and to learn more about the in vivo functions of these DNA repair factors. Previous studies of NHEJ-deficient mice have provided significant mechanistic insights into the functions of the NHEJ factors in immune system development as well as in suppressing oncogenic chromosomal events that predispose the mutant mice to lymphoid neoplasias. Currently, we are using a combination of biochemical, cellular and genetic approaches to gain additional insights into the specific functions and activities of the NHEJ factors during DNA repair and lymphocyte development. We are particularly interested further characterizing the NHEJ gene, Artemis, as recent evidence suggests that different mutations cause distinct disease outcomes in human patients. Specifically, inactivating mutations in Artemis cause a human severe combined immunodeficiency associated with extreme cellular radiosensitivity and hypomorphic mutations are associated with predisposition to lymphoid neoplasia.

Project 1: Examine the roles of the human disease gene, Artemis, a DNA repair factor with roles in tumor suppression, immune system development, DNA double strand break repair, maintaining genomic stability and telomere maintenance. In vitro and/or in vivo analyses with a focus on mutant forms of Artemis found associated with lymphoma in human patients.

Project 2: Determine the effects of mutated forms of the RAG1/RAG2 endonuclease on immune system development, genomic stability and predisposition to tumorigenesis. In vivo analyses of specific knock-in mutations of RAG1 and RAG2 in mice.

Project 3: Examine the in vitro activities and/or in vivo functions of DNA repair enzymes related to Artemis involved in DNA interstrand crosslink resolution and potentially other repair processes.